Deuterium-enriched isoindolinonyl-piperidinonyl conjugates and oxoquinazolin-3(4H)-yl-piperidinonyl conjugates and methods of treating medical disorders using same

ABSTRACT

The invention provides deuterium-enriched isoindolinonyl-piperidinonyl conjugates, deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonyl conjugates, pharmaceutical compositions, and methods of using such conjugates and pharmaceutical compositions to treat cancer, angiogenesis disorders, immune disorders, and other medical disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/240,499, filed Aug. 18, 2016, which claims the benefit of andpriority to U.S. Provisional Patent Application Ser. No. 62/206,396,filed Aug. 18, 2015, the contents of each of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention provides deuterium-enriched isoindolinonyl-piperidinonylconjugates, deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonylconjugates, pharmaceutical compositions, and methods of using suchconjugates and pharmaceutical compositions to treat cancer and othermedical disorders.

BACKGROUND

Cancer remains a substantial challenge to human health. Cancer isfrequently characterized by an increase in the number of abnormal cellsderived from a given normal tissue. Exemplary cancers that impact asubstantial percentage of the patient population include, for example,cancer of the lung, colon, rectum, prostate, breast, and blood. Theincidence of cancer continues to increase as the general populationages, new cancers develop, and susceptible populations (e.g., peopleinfected with AIDS) grow. Notwithstanding the significant need forcancer therapy, options for the treatment of cancer are limited. Forexample, in the case of blood cancers (e.g., multiple myeloma), fewtreatment options are available, especially when conventionalchemotherapy fails and bone marrow transplantation is not an option. Asubstantial demand therefore exists for new methods and compositionsthat can be used to treat patients with cancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. One mechanism is thesecretion by tumor cells of cytokines with angiogenic properties.Examples of these cytokines include acidic and basic fibroblastic growthfactor (bFGF), angiogenin, vascular endothelial growth factor (VEGF),and TNF-α. Alternatively, tumor cells can release angiogenic peptidesthrough the production of proteases and the subsequent breakdown of theextracellular matrix where some cytokines are stored. Angiogenesis canalso be induced indirectly through the recruitment of inflammatory cells(particularly macrophages) and the subsequent release of angiogeniccytokines (e.g., TNF-α, bFGF). A variety of disorders are alsoassociated with undesired angiogenesis. Thus, a need exists for improvedmethods and agents for inhibiting angiogenesis.

The present invention addresses these unmet needs and providesadditional advantages.

SUMMARY

The invention provides deuterium-enriched isoindolinonyl-piperidinonylconjugates, deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonylconjugates, pharmaceutical compositions, and methods of treating medicaldisorders using a deuterium-enriched isoindolinonyl-piperidinonylconjugate or deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonylconjugate described herein. The deuterium-enrichedisoindolinonyl-piperidinonyl conjugates and deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugates contain deuteriumenrichment at the chiral center of the piperidine-2,6-dione group andoptionally at other locations of the conjugate. Further, thedeuterium-enriched isoindolinonyl-piperidinonyl conjugates anddeuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonyl conjugates maybe provided in enantiomerically pure form. These features arecontemplated to provide therapeutic agents with improved properties.

Accordingly, one aspect of the invention provides a deuterium-enrichedcompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. In certain embodiments, thedeuterium-enriched compound is a compound of Formula I-1 represented by:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula II represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula III represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula IV represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula V represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In another aspect, the invention provides a pharmaceutical compositioncomprising a deuterium-enriched isoindolinonyl-piperidinonyl conjugateor a deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonyl conjugatedescribed herein and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of treating a medicaldisorder described herein, such as a disorder selected from the groupconsisting of cancer, an immune disorder, and an inflammatory disorder.The method comprises administering to a patient in need thereof atherapeutically effective amount of a deuterium-enrichedisoindolinonyl-piperidinonyl conjugate or a deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugate described herein, such asa deuterium-enriched compound of Formula I, II, III, IV, or V, to treatthe disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a line graph showing relative peak areas of the enantiomers ofprotonated dBET1 (area(enantiomer)/sum of areas) as function of timeupon incubation in PBS (pH=7.4) at 25° C., as further described inExample 3.

FIG. 2 provides mass spectroscopy plots showing mass spectral isotopicratio for deuterium-enriched dBET1 (D-dBET1) incubated in PBS (pH=7.4)at 25° C., where FIG. 2 Part A is for time=0 hours and FIG. 2 Part B isfor time=24 hours, each in positive ion mode with 785 and 807 themolecular weight of protonated dBET1+one proton and protonated dBET1+onesodium, respectively, as further described in Example 3.

DETAILED DESCRIPTION

The invention provides deuterium-enriched isoindolinonyl-piperidinonylconjugates, deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonylconjugates, pharmaceutical compositions, and methods of treating medicaldisorders using a deuterium-enriched isoindolinonyl-piperidinonylconjugate or deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonylconjugate described herein. The deuterium-enrichedisoindolinonyl-piperidinonyl conjugates and deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugates described herein containdeuterium enrichment at the chiral center of the piperidine-2,6-dionegroup and optionally at other locations of the conjugate. Deuteriumenrichment at the chiral center reduces the rate at which the twoenantiomers of the piperidine-2,6-dione group may interconvert. Further,the deuterium-enriched isoindolinonyl-piperidinonyl conjugates anddeuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonyl conjugates maybe provided in enantiomerically pure form. These features arecontemplated to provide therapeutic agents with improved properties.

Deuterium-enriched refers to the feature that the compound has aquantity of deuterium that is greater than in naturally occurringcompounds or synthetic compounds prepared from substrates having thenaturally occurring distribution of isotopes. The threshold amount ofdeuterium enrichment is specified in certain instances in thisdisclosure, and all percentages given for the amount of deuteriumpresent are mole percentages.

Deuterium (²H) is a stable, non-radioactive isotope of ¹H hydrogen andhas an atomic weight of 2.014. Hydrogen naturally occurs as a mixture ofthe isotopes ¹H hydrogen (i.e., protium), deuterium (²H), and tritium(³H). The natural abundance of deuterium is 0.015%. One of ordinaryskill in the art recognizes that in all chemical compounds with an Hatom, the H atom actually represents a mixture of ¹H hydrogen, deuterium(²H), and tritium (³H), where about 0.015% is deuterium. Thus, compoundswith a level of deuterium that has been enriched to be greater than itsnatural abundance of 0.015% are considered unnatural and, as a result,novel over their non-enriched counterparts.

Exemplary compositions and methods of the present invention aredescribed in more detail in the following sections: I.Deuterium-enriched Isoindolinonyl-piperidinonyl andOxoquinazolin-3(4H)-yl-piperidinonyl Conjugates; II. TherapeuticApplications; III. Dosing Considerations and Combination Therapy, andIV. Pharmaceutical Compositions. Aspects of the invention described inone particular section are not to be limited to any particular section.

I. Deuterium-enriched Isoindolinonyl-piperidinonyl andOxoquinazolin-3(4H)-yl-piperidinonyl Conjugates

One aspect of the invention provides deuterium-enriched compounds foruse in the therapeutic methods and pharmaceutical compositions describedherein. As explained above, the deuterium-enrichedisoindolinonyl-piperidinonyl conjugates and deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugates described herein containdeuterium enrichment at the chiral center of the piperidine-2,6-dionegroup. Deuterium enrichment at the chiral center reduces the rate atwhich the two enantiomers of the piperidine-2,6-dione group mayinterconvert.

Accordingly, one aspect of the invention provides a deuterium-enrichedcompound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is H or D, provided that the abundance of deuterium in Z is at        least 30%;    -   X¹ is —CH₂—, —C(O)—, or ψ-C(CH₃)═N—, where ψ is a bond to the        amide nitrogen atom;    -   X² is —N(R¹)—, —O—, —(C₁-C₂)-alkylene-N(R¹)—, or        —(C₁-C₂)-alkylene-O—;    -   Y¹ is a 3-30 membered alkylene or 3-30 membered heteroalkylene,        each of which is optionally substituted by one or more R²;    -   R¹ is hydrogen or —(C₁-C₄)-alkyl;    -   R² represents independently for each occurrence oxo,        —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, halogen,        —(C₁-C₆)-haloalkyl, hydroxyl, —(C₁-C₆)-alkoxyl, or        —(C₁-C₆)-hydroxyalkyl; or    -   two occurrences of R² are taken together with the intervening        atom or atoms to form a 3-8 membered ring;    -   A¹ is a protein binding moiety having a molecular weight of less        than 2500 g/mol; and    -   any hydrogen atom may be optionally replaced with D.

In certain embodiments, the compound is a compound of Formula I.

In certain embodiments, the compound is a compound of Formula I-1represented by:

or a pharmaceutically acceptable salt thereof, wherein the definition ofvariables Z, X¹, X², Y¹ and A¹ are as provided for Formula I above.

In certain embodiments, the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the definition of variables Z, X¹,X², Y¹ and A¹ are as provided for Formula I above.

In certain embodiments, the compound is a compound of Formula I-A.

In certain embodiments, the compound is a compound of Formula I-A1represented by:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the definition of variables Z, X¹,X², Y¹ and A¹ are as provided for Formula I above.

In certain embodiments, the compound is a compound of Formula I-A1.

In certain embodiments, the compound is represented by Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the definition of variables Z, X¹,X², Y¹ and A¹ are as provided for Formula I above.

In certain embodiments, the compound is a compound of Formula I-B.

In certain embodiments, the compound is a compound of Formula I-B1represented by:

or a pharmaceutically acceptable salt thereof, wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z, and the definition of variables Z, X¹,X², Y¹ and A¹ are as provided for Formula I above.

In certain embodiments, the compound is a compound of Formula I-B1.

Each of Formula I, I-1, I-A, I-A1, I-B, and I-B1 may be furtherdescribed according to one or more of the definitions for Z, X¹, X², Y¹and A¹ provided below. In particular, collections of compounds definedby combinations of particular definitions (provided below) for each ofZ, X¹, X², Y¹ and A¹ are contemplated.

In certain embodiments, X¹ is —CH₂—, —C(O)—, or ψ-C(CH₃)═N—, where ψ isa bond to the amide nitrogen atom. In certain embodiments, X¹ is —C(O)—.In certain embodiments, X¹ is ψ-C(CH₃)═N—, where ψ is a bond to theamide nitrogen atom.

In certain embodiments, X² is —N(R¹)—. In certain embodiments, X² is—O—.

In certain embodiments, X² is —(C₁-C₂)-alkylene-N(R¹)— or—(C₁-C₂)-alkylene-O—.

In certain embodiments, Y¹ is a 3-30 membered heteroalkylene optionallysubstituted by one or more R². In certain embodiments, Y¹ is a 10-20membered heteroalkylene optionally substituted by 1, 2, 3, or 4 R². Moregenerally, variable Y¹ represents a linking group between proteinbinding moiety A¹ and variable X². Exemplary linking groups contemplatedfor use in the present deuterium-enriched conjugates include thosedescribed in U.S. Patent Application Publication US 2015/0119435, whichis hereby incorporated by reference. In certain embodiments, Y¹ is oneof the following:

In certain other embodiments, Y¹ is one of the following:

In certain embodiments, the heteroalkylene contains 2, 3, 4, 5, 6, 7, or8 heteroatoms independently selected from oxygen and nitrogen. Incertain embodiments, the heteroalkylene is a 3-30 memberedheteroalkylene that contains 2, 3, 4, 5, 6, 7, or 8 heteroatomsindependently selected from oxygen and nitrogen. In certain embodiments,the heteroalkylene is a 3-30 membered heteroalkylene that contains 2, 3,4, 5, 6, 7, or 8 heteroatoms independently selected from oxygen andnitrogen, and the heteroalkylene is substituted by substituted by 1, 2,3, or 4 R² where R² is independently for each occurrence oxo or—(C₁-C₆)-alkyl.

In certain embodiments, R² is oxo. In certain embodiments, R² representsindependently for each occurrence oxo, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl or halogen.

In certain embodiments, the abundance of deuterium in Z is at least 60%.In certain embodiments, the abundance of deuterium in Z is at least 75%.In certain embodiments, the abundance of deuterium in Z is at least 90%.In certain embodiments, the abundance of deuterium in Z is at least 95%.

In certain embodiments, A¹ is a protein binding moiety having amolecular weight of less than 2500 g/mol that has one or more of thefollowing features:

-   -   a. inhibits BRD2;    -   b. inhibits BRD3;    -   c. inhibits BRD4;    -   d. inhibits Bcr-Abl;    -   e. inhibits dihydrofolate reductase;    -   f. binds to tau neurofibril;    -   g. inhibits HSP90;    -   h. inhibits a kinase;    -   i. inhibits MDM2;    -   j. inhibits HDAC;    -   k. inhibits human lysine methyl transferase;    -   l. binds to or modulates the activity of an estrogen receptor;        or    -   m. binds to or modulates the activity of retinoid-related orphan        receptor alpha.

In certain embodiments, A¹ is one of the following:

In certain embodiments, A¹ is one of the following:

More generally, variable A¹ represents a protein binding moiety suitablefor use in deuterium-enriched conjugates. Exemplary protein bindingmoieties contemplated for use in the present deuterium-enrichedconjugates include those described in U.S. Patent ApplicationPublication US 2015/0119435, which is hereby incorporated by reference.In certain embodiments, the protein binding moiety is a moiety thatbinds to a target protein that comprises one or more of the following:B7, B7-1, TINFR1m, TNFR2, NADPHoxidase, Bcl1Bax (or another partner inthe apoptosis pathway), a C5a receptor, HMGCoA reductase, PDE Vphosphodiesterase type, PDE IV phosphodiesterase type 4, PDE L, PDE II,PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO)synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, a 5HT receptor, adopamine receptor, a G Protein, a histamine receptor, 5-lipoxygenase,tryptase serine protease, thymidylate synthase, purine nucleosidephosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonicanhydrase, a chemokine receptor, JAW STAT, RXR, HIV 1 protease, HIV 1integrase, influenza neuraminidase, hepatitis B reverse transcriptase,sodium channel, protein P-glycoprotein (and MRP), tyrosine kinases,CD23, CD124, tyrosine kinase p561ck, CD4, CDS, IL-2 receptor, IL-1receptor, TNF-alphaR, ICAM1, Ca²⁺ channels, VCAM, VLA-4 integrin,selectins, CD40/CD40L, neurokinins and receptors, inosine monophosphatedehydrogenase, p38 MAP Kinase, Ras1Raf1MEWERK pathway, interleukin-1converting enzyme, caspase, HCV NS3 protease, HCV NS3 RNA helicase,glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease,herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease,poly (ADP-ribose) polymerase, cyclin dependent kinases, vascularendothelial growth factor, oxytocin receptor, microsomal transferprotein inhibitor, bile acid transport inhibitor, a 5 alpha reductaseinhibitor, angiotensin 11, glycine receptor, noradrenaline reuptakereceptor, an endothelin receptor, neuropeptide Y and receptor, anadenosine receptor, adenosine kinase and AMP deaminase, a purinergicreceptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), a farnesyltransferase, ageranylgeranyl transferase, a TrkA receptor for NGF, β-amyloid, tyrosinekinase Flk-IIKDR, a vitronectin receptor, an integrin receptor, Her-21neu, telomerase inhibition, tumor associated protein (IMP), Bcr-Abltyrosine kinase, cytosolic phospholipase A2, EGF receptor tyrosinekinase, ecdysone 20-monooxygenase, ion channel of the GABA gatedchloride channel, acetylcholinesterase, voltage-sensitive sodium channelprotein, calcium release channel, chloride channel, acetyl-CoAcarboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase,enolpyruvylshikimate-phosphate synthase, or a drug resistant andmultiple drug resistance (MDR) protein. In certain embodiments, thetarget protein comprises Bcr-Abl tyrosine kinase, dihydrofolatereductase, p38 kinase, checkpoint kinase 2, RAF kinase, VEGFR2, VEGFR3,ALK (anaplastic lymphoma kinase), Aurora kinase, Janus kinase 2 (JAK2),protein tyrosine phosphatase, SHP-2 domain of protein tyrosinephosphatase, mitogen activated protein kinase (BRAF^(v600E)/MEK), MDM2ubiquitin ligase, human BET bromodomain-containing protein Brd2, Brd3,Brd4, and Skpl-Cullin-F box complex, HSP90, HSP70, VEGF, ubiquitinligase, histone deacetylase protein (HDAC), lysine methyltransferase,aryl hydrocarbon receptor, estrogen receptor, FK506 binding protein(FKBP), thyroid hormone receptor (THR), HIV protease, HIV integrase, HCVprotease, acyl-protein thioesterase 1 and 2 (APT1 andAPT2), tyrosinekinase p56 lck, EGF receptor tyrosine kinase, tyrosine kinase Flk-IIKDRor a tumor-associated membrane protein (TMP).

In certain embodiments, the deuterium-enriched compound is a compound ofFormula II represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula II-A represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula II-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is representedby:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula III represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula III-A represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula III-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is representedby:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula IV represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula IV-A represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula IV-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is representedby:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula V represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula V-A represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is a compound ofFormula V-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.

In certain embodiments, the deuterium-enriched compound is representedby:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.

Deuterium-enriched compounds of the above Formulae (e.g., Formula I,I-1, I-A, I-A 1, I—B, I—B1, II, II-A, II-B, III, III-A, III-B, IV, IV-A,IV-B, V, V-A, and V-B) may be further characterized according to theextent of deuterium enrichment at the position defined by variable Zand/or the stereochemical purity of the compound at the position definedby variable Z. For example, in certain embodiments, the abundance ofdeuterium in Z is at least 60%. In certain other embodiments, theabundance of deuterium in Z is at least 75%. In yet other embodiments,the abundance of deuterium in Z is at least 90%. In yet otherembodiments, the abundance of deuterium in Z is at least 95%. In yetother embodiments, the abundance of deuterium in Z is from about 80% toabout 99%, about 85% to about 99%, or about 90% to about 99%. In yetother embodiments, the abundance of deuterium in Z is selected from: (a)at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e)at least 75%, (f) at least 80%, (g) at least 90%, (h) at least 95%, (i)at least 97%, and (j) about 100%. Additional examples of the abundanceof deuterium in Z include about 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99 to about 100%.

In certain embodiments, the compound has a stereochemical purity of atleast 85% enantiomeric excess at the carbon atom bearing variable Z. Incertain other embodiments, the compound has a stereochemical purity ofat least 90% enantiomeric excess at the carbon atom bearing variable Z.In certain other embodiments, the compound has a stereochemical purityof at least 95% enantiomeric excess at the carbon atom bearing variableZ. In certain other embodiments, the compound has a stereochemicalpurity of at least 98% enantiomeric excess at the carbon atom bearingvariable Z. In certain other embodiments, the compound has astereochemical purity of at least 99% enantiomeric excess at the carbonatom bearing variable Z. In other embodiments, the deuterium-enrichedcompound has a stereochemical purity of at least 80%, 85%, 90%, 95%, or98% enantiomeric excess at a chiral carbon atom bearing variable Z, andyet additional examples of stereochemical purity include an enantiomericexcess of at least 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% at achiral carbon atom bearing variable Z.

In yet other embodiments, the deuterium-enriched compound may containstereogenic centers in addition to the stereogenic center at the carbonatom bearing variable Z, and such deuterium-enriched compounds may beprovided in stereochemically pure form, such as where the compound hasan overall stereochemical purity of at least 90%, 95%, 98% or 99%, whichmay be expressed as a diastereomeric excess of at least 90%, 95%, 98% or99%.

In yet other embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain embodiments, the foregoing compounds are provided instereochemically pure form, such as having an enantiomeric excess or adiastereomeric excess greater than 90%, 95%, 98% or 99%. In certainembodiments, the predominant stereoisomer has the R-configuration at thecarbon atom bearing D. In certain other embodiments, the predominantstereoisomer has the S-configuration at the carbon atom bearing D.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a deuterium-enriched compound described hereinand a pharmaceutically acceptable carrier.

Deuterium-enriched compounds of the invention can generally be preparedby substituting a deuterium-enriched reagent for a non-isotopicallylabeled reagent in synthetic schemes reported in the literature formaking non-isotopically labeled isoindolinonyl-piperidinonyl conjugatesor oxoquinazolin-3(4H)-yl-piperidinonyl conjugates. Publicationsdescribing methods for preparing non-isotopically labeled compounds ofthese types, and which also describe compounds that may be used in thepresent invention, include, for example, U.S. Pat. Nos. 5,635,517,6,335,349, and 7,994,327; U.S. Pat. Nos. 9,067,912 and 7,635,700(oxoquinazolin-3(4H)-yl compounds), and U.S. Patent Publication No.2011/0196150, U.S. Pat. No. 8,518,972, and WO 2011/100380(oxo-isoindolinyl compounds), which are hereby incorporated byreference. Furthermore, deuterated 1,3-dioxoisoindolin-4-yl compoundsand synthetic methods for their preparation are described, for example,in U.S. Pat. No. 9,090,585, which is hereby incorporated by reference inits entirety. Deuterated oxoquinazolin-3(4H)-yl compounds and syntheticmethods for their preparation are described, for example, in U.S. PatentPublication Nos. 2014/0288101 and 2014/0228382, which are herebyincorporated by reference. Deuterated oxo-isoindolinyl compounds andsynthetic methods for their preparation are described, for example, inU.S. Pat. No. 8,288,414, which is hereby incorporated by reference.Schemes 1 and 2 below illustrate a general method for preparingdeuterium-enriched isoindolinonyl-piperidinonyl conjugates,deuterium-enriched oxoquinazolin-3(4H)-yl-piperidinonyl conjugates, andrelated compounds enriched with deuterium at one or more positions. Theschemes and descriptions below are provided for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention.

As shown in Scheme 1, the preparation of a deuterium-enrichedisoindolinonyl-piperidinonyl conjugate or deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugate begins with the couplingof intermediate A (a protein-binding moiety) to linker moiety B to formintermediate C. Exemplary coupling conditions include those described inthe literature for amide bond formation, which may include using one ormore of the following reagents in an amide coupling reaction: EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), HOBT(hydroxybenzotriazole), or HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate). Reaction of intermediate C withdeuterium-enriched compound D provides final product E. Group X^(B) oncompound D and group X^(A) on compound C are selected so as to undergo achemical reaction to form a covalent linkage, such as amide linkage.Group X^(A) may be protected using a protecting group (such as any ofthe standard protecting groups known in the literature of protecting acarboxylic acid group), where the protecting group is removed prior toreaction of compound C with compound D.

Compound E and related compounds may be used in racemic form or they maybe synthesized in enantioenriched form, e.g., by employing D inenantioenriched form. As shown in Scheme 2, the R-enantiomer andS-enantiomer of E may be may be separated by chiral chromatography, suchas chiral high-performance liquid chromatography, to yield F and F′.Alternatively, the R-enantiomer and S-enantiomer of E may be separatedby reaction with a chiral carboxylic acid to form a salt, followed byseparation of the resulting diastereomeric salts, and conversion of theseparated salts back to the deuterated free base in enantiopure form.

Compounds having deuterium enrichment at a position other than thosespecifically mentioned above can be prepared by selecting an appropriatedeuterium-enriched starting material, or by known methods of introducinga deuterium atom or exchanging a proton for a deuteron that are known inthe art.

Compounds described herein can be provided in isolated or purified form.Isolated or purified compounds are a group of compounds that have beenseparated from their environment, such as from a crude reaction mixtureif made in a laboratory setting or removed from their naturalenvironment if naturally occurring. Examples of the purity of theisolated compound include, for example, at least 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, to 100% by weight.

Another aspect of the invention provides a unit quantum of adeuterium-enriched compound described herein, such as an amount of atleast (a) one μg of a disclosed deuterium-enriched compound, (b) one mg,or (c) one gram. In further embodiments, the quantum is, for example, atleast 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, or 1 moleof the compound. The present amounts also cover lab-scale (e.g., gramscale including 1, 2, 3, 4, 5 g, etc.), kilo-lab scale (e.g., kilogramscale including 1, 2, 3, 4, 5 kg, etc.), and industrial or commercialscale (e.g., multi-kilogram or above scale including 100, 200, 300, 400,500 kg, etc.) quantities as these will be more useful in the actualmanufacture of a pharmaceutical. Industrial/commercial scale refers tothe amount of product that would be produced in a batch that wasdesigned for clinical testing, formulation, sale/distribution to thepublic, etc.

II. Therapeutic Applications

The invention provides methods of using deuterium-enriched conjugatesdescribed herein to treat medical disorders. The deuterium-enrichedconjugate can be, for example, a compound of Formula I, II, III, IV, orV, or one of the other deuterium-enriched compounds described in SectionI above. Various aspects of the invention pertaining to treating medicaldisorders are described below.

Accordingly, one aspect of the invention provides a method of treating amedical disorder in a patient. The method comprises administering to apatient in need thereof a therapeutically effective amount of a compounddescribed herein, such as a deuterium-enriched compound described inSection 1 above, to treat the disorder. The disorder may be, forexample, selected from the group consisting of cancer, an immunedisorder, and an inflammatory disorder. In certain embodiments, thedisorder is cancer (e.g., a cancer of the bladder, bone, blood, brain,breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney,liver, lymph node, lung, mouth, neck, ovary, pancreas, prostate, rectum,stomach, testis, throat, or uterus.)

Without being limited by a particular theory, compounds provided hereinare expected to control angiogenesis or inhibit the production ofcertain cytokines. Further, compounds provided herein may beimmunomodulatory and/or cytotoxic, and thus, may be useful aschemotherapeutic agents. Consequently, without being limited by aparticular theory, some or all of such characteristics possessed by thecompounds provided herein may render them useful in treating variousdiseases or disorders. For example, enhanced or unregulated angiogenesishas been implicated in a number of diseases and medical conditionsincluding, but not limited to, ocular neovascular diseases, choroidalneovascular diseases, retina neovascular diseases, rubeosis(neovascularization of the angle), viral diseases, genetic diseases,inflammatory diseases, allergic diseases, fibrosis, arthritis andautoimmune diseases. Further examples of such diseases and conditionsinclude, but are not limited to: diabetic retinopathy; retinopathy ofprematurity; corneal graft rejection; neovascular glaucoma; retrolentalfibroplasia; and proliferative vitreoretinopathy.

Still further exemplary diseases or disorders include, but are notlimited to, cancer, disorders associated with angiogenesis, painincluding, but not limited to, Complex Regional Pain Syndrome (“CRPS”),Macular Degeneration (“MD”) and related syndromes, skin diseases,pulmonary disorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders (including tauopathies), CNSinjury, atherosclerosis and related disorders, dysfunctional sleep andrelated disorders, hemoglobinopathy and related disorders (e.g.,anemia), TNF-α related disorders, amyloidoses, and other variousdiseases and disorders.

Examples of cancer and precancerous conditions that may be treated bythe present methods include, but are not limited to, those described inU.S. Pat. Nos. 6,281,230 and 5,635,517 to Muller et al., in various U.S.patent publications to Zeldis, including U.S. Patent Publication Nos.2004/0220144A1, published Nov. 4, 2004 (Treatment of MyelodysplasticSyndrome); 2004/0029832A1, published Feb. 12, 2004 (Treatment of VariousTypes of Cancer); and 2004/0087546, published May 6, 2004 (Treatment ofMyeloproliferative Diseases). Examples also include those described inWO 2004/103274, published Dec. 2, 2004. All of these references areincorporated herein in their entireties by reference.

Specific examples of cancer that may be treated by the present methodsinclude, but are not limited to, cancers of the skin, such as melanoma;lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary;prostate; colon; rectum; mouth; brain; head and neck; throat; testes;kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages;and AIDS-related cancers. The compounds are also useful for treatingcancers of the blood and bone marrow, such as multiple myeloma and acuteand chronic leukemias, for example, lymphoblastic, myelogenous,lymphocytic, and myelocytic leukemias. The compounds provided herein canbe used for treating, preventing or managing either primary ormetastatic tumors.

Other specific cancers that may be treated by the present methodinclude, but are not limited to, advanced malignancy, amyloidosis,neuroblastoma, meningioma, hemangiopericytoma, multiple brainmetastases, glioblastoma multiforme, glioblastoma, brain stem glioma,poor prognosis malignant brain tumor, malignant glioma, recurrentmalignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,neuroendocrine tumor, rectal adenocarcinoma, Dukes C colorectal cancer,Dukes D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, acute myeloblastic leukemia,chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuselarge B-cell lymphoma, low grade follicular lymphoma, metastaticmelanoma (localized melanoma, including, but not limited to, ocularmelanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressiva, hormone-refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen-independentprostate cancer, androgen-dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another aspect, the cancer isrefractory or resistant to chemotherapy or radiation.

Accordingly, in certain embodiments, the cancer is an advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes Ccolorectal cancer, Dukes D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acutemyeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse largeB-Cell lymphoma, low grade follicular lymphoma, malignant melanoma,malignant mesothelioma, malignant pleural effusion mesotheliomasyndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologicsarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressive, hormone-refractory prostate cancer, resected high-risk softtissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen-independent prostate cancer, androgen-dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.In certain other embodiments, the cancer is a cancer of the bladder,bone, blood, brain, breast, cervix, chest, colon, endometrium,esophagus, eye, head, kidney, liver, lymph node, lung, mouth, neck,ovary, pancreas, prostate, rectum, stomach, testis, throat, or uterus.

In certain embodiments, the cancer is a solid tumor or a blood-bornetumor. The solid tumor and/or blood-borne tumor may be metastatic and/ordrug resistant. In certain embodiments, the cancer is myeloma orlymphoma. In certain embodiments, the solid tumor is a hepatocellularcarcinoma, glioblastoma, prostate cancer, colorectal cancer, ovariancancer, or renal cancer.

In certain embodiments, the cancer is a non-Hodgkin's lymphoma that is adiffuse large B-cell lymphoma (such as characterized as being anactivated B-cell phenotype). In yet other embodiments, the cancer is anon-Hodgkin's lymphoma that is a diffuse large B-cell lymphomacharacterized by the expression of one or more biomarkers overexpressedin RIVA, U2932, TMD8, or OCI-Ly10 cell lines.

In certain embodiments, the cancer is relapsed or refractory.

In another aspect, provided herein are methods of treating various formsof leukemias such as chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia andacute myeloblastic leukemia, including leukemias that are relapsed,refractory or resistant, as disclosed in U.S. Patent Publication No.2006/0030594, published Feb. 9, 2006, which is incorporated in itsentirety by reference.

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another aspect, provided herein are methods of treating various typesof lymphomas, including Non-Hodgkin's lymphoma (NHL). The term“lymphoma” refers to a heterogeneous group of neoplasms arising in thereticuloendothelial and lymphatic systems. “NHL” refers to malignantmonoclonal proliferation of lymphoid cells in sites of the immunesystem, including lymph nodes, bone marrow, spleen, liver andgastrointestinal tract. Examples of NHL include, but are not limited to,mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediatedifferentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorlydifferentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffusesmall-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any typeof the mantle cell lymphomas that can be seen under the microscope(nodular, diffuse, blastic and mantle zone lymphoma).

Additional exemplary diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, inflammatory diseases, autoimmune diseases, viral diseases, geneticdiseases, allergic diseases, bacterial diseases, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,and rubeosis iridis (neovascularization of the angle of the eye).Specific examples of the diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, arthritis, endometriosis, Crohn's disease, heart failure, advancedheart failure, renal impairment, endotoxemia, toxic shock syndrome,osteoarthritis, retrovirus replication, wasting, meningitis,silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder,malignancy-associated hypercalcemia, stroke, circulatory shock,periodontitis, gingivitis, macrocytic anemia, refractory anemia, and5q-deletion syndrome.

In certain embodiments, the disorder to be treated is an immune diseaseor an inflammatory disease. In certain other embodiments, the disorderto be treated is systemic lupus erythematosus, scleroderma, Sjogren'ssyndrome, ANCA-induced vasculitis, anti-phospholipid syndrome, ormyasthenia gravis. The scleroderma may be localized, systemic, limited,or diffuse scleroderma. In certain embodiments, the systemic sclerodermacomprises CREST syndrome (Calcinosis, Raynaud's syndrome, esophagealdysfunction or dysmotility, sclerodactyly, telangiectasia). Sclerodermais also known as systemic sclerosis or progressive systemic sclerosis.In certain embodiments, systemic sclerosis comprises scleroderma lungdisease, scleroderma renal crisis, cardiac manifestations, muscularweakness (including fatigue or limited CREST), gastrointestinaldysmotility and spasm, and abnormalities in the central, peripheral andautonomic nervous system (including carpal tunnel syndrome followed bytrigeminal neuralgia). It also includes general disability, includingdepression, and impact on quality of life. In certain embodiments,limited scleroderma is limited to the hands, the face, neck, orcombinations thereof. In certain embodiments, diffuse sclerodermacomprises skin tightening and also occurs above the wrists (or elbows).In yet other embodiments, diffuse systemic sclerosis is sinescleroderma, comprising internal organ fibrosis, but no skin tightening;or familial progressive systemic sclerosis.

In certain embodiments, the disorder to be treated is Raynaud's diseaseor syndrome.

Another aspect of the invention provides a method for treating a symptomof systemic lupus erythematosus by administering to a patient sufferingfrom systemic lupus erythematosus a deuterium-enriched compounddescribed herein, wherein the symptom is one or more of joint pain,joint swelling, arthritis, chest pain when taking a deep breath,fatigue, fever with no other cause, general discomfort, uneasiness, hairloss, mouth sores, swollen lymph nodes, sensitivity to sunlight, skinrash, headaches, numbness, tingling, seizures, vision problems,personality changes, abdominal pain, nausea, vomiting, abnormal heartrhythms, coughing up blood, difficulty breathing, patchy skin color, orRaynaud's phenomenon.

Another aspect of the invention provides a method for treating a symptomof scleroderma by administering to a patient suffering from sclerodermaa deuterium-enriched compound described herein, wherein the symptom isone or more of (i) gradual hardening, thickening, and tightening of theskin; (ii) skin discoloration; (iii) numbness of extremities; (iv) shinyskin; (v) small white lumps under the surface of the skin that eruptinto a chalky white fluid; (vi) Raynaud's esophageal dysfunction; (vii)telangiectasia; (viii) pain and/or stiffness of the joints; (ix)swelling of the hands and feet; (x) itching of the skin; (xi) stiffeningand curling of the fingers; (xii) ulcers on the outside of certainjoints, such as knuckles and elbows; (xiii) digestive problems, such asheartburn, difficulty swallowing, diarrhea, irritable bowel, andconstipation; (xiv) fatigue and weakness; (xv) shortness of breath;(xvi) arthritis; (xvii) hair loss; (xviii) internal organ problems;(xix) digital ulcers; and (xx) digital auto-amputation.

Another aspect of the invention provides a method for improving themodified Rodnan skin score, reducing or improving the skin thickness,reducing or improving skin induration, improving the pulmonary function,improving the dermatology quality of life index, improving the carbonmonoxide diffusing capacity, improving the Mahler Dyspnea index,improving the Saint George's Respiratory Questionnaire score, improvingthe UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tractscore, improving flow-mediated dilatation, or improving or increasingthe six minute walk distance of a patient having scleroderma, comprisingadministering to the patient an effective amount of a deuterium-enrichedcompound described herein.

Another aspect of the invention provides a method for modulatingactivity of a cell selected from the group consisting of a B cell and aT cell, comprising contacting the cell with an effective amount of adeuterium-enriched compound described herein to modulate the activity ofthe cell.

Another aspect of the invention provides a method for treating animmune-related disorder or a disorder selected from the group consistingof Sjogren's syndrome, ANCA-induced vasculitis, myasthenia gravis,Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid-antibody syndrome, antiphospholipid syndrome (primaryor secondary), asthma, autoimmune gastritis, autoimmune hemolyticanemia, autoimmune hepatitis, autoimmune inner-ear disease, autoimmunelymphoproliferative disease, autoimmune thrombocytopenic purpura, Balodisease, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiacdisease, Chagas disease, chronic inflammatory demyelinatingpolyneuropathy, cicatrical pemphigoid (e.g., mucous membranepemphigoid), cold agglutinin disease, Degos disease, dermatitishepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome,Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis(Hashimoto's disease; autoimmune thyroiditis), idiopathic pulmonaryfibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, juvenilearthritis, lichen planus, Ménière's disease, mixed connective-tissuedisease, morphea, narcolepsy, neuromyotonia, pediatric autoimmuneneuropsychiatric disorders associated with streptococcal infection(PANDAs), pemphigus vulgaris, pernicious anemia, polyarteritis nodosa,polychondritis, polymyalgia rheumatica, primary agammaglobulinemia,primary biliary cirrhosis, Raynaud's disease (Raynaud's phenomenon),Reiter's syndrome, relapsing polychondritis, rheumatic fever, Sjogren'ssyndrome, stiff-person syndrome (Moersch-Woltmann syndrome), Takayasu'sarteritis, temporal arteritis (giant cell arteritis), uveitis,vasculitis (e.g., vasculitis not associated with lupus erythematosus),vitiligo, and Wegener's granulomatosis. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a deuterium-enriched compound described herein to treat thedisorder.

Another aspect of the invention provides a method of treating pain in asubject, comprising administering to a patient in need thereof atherapeutically effective amount of a deuterium-enriched compounddescribed herein. Exemplary types of pain include nociceptive pain,neuropathic pain, mixed pain of nociceptive and neuropathic origin,visceral pain, migraine, headache and post-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, complexregional pain syndrome (CRPS) type I, CRPS type II, reflex sympatheticdystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy,sympathetically maintained pain syndrome, causalgia, Sudeck's atrophy ofbone, algoneurodystrophy, shoulder hand syndrome, post-traumaticdystrophy, trigeminal neuralgia, post-herpetic neuralgia, cancer-relatedpain, phantom-limb pain, fibromyalgia, chronic fatigue syndrome, spinalcord injury pain, central post-stroke pain, radiculopathy, diabeticneuropathy, post-stroke pain, luetic neuropathy, and other painfulneuropathic conditions such as those induced by drugs such asvincristine and velcade.

Complex regional pain syndrome (CRPS) and CRPS and related syndromesmean a chronic pain disorder characterized by one or more of thefollowing: pain, whether spontaneous or evoked, including allodynia(painful response to a stimulus that is not usually painful) andhyperalgesia (exaggerated response to a stimulus that is usually onlymildly painful); pain that is disproportionate to the inciting event(e.g., years of severe pain after an ankle sprain); regional pain thatis not limited to a single peripheral nerve distribution; and autonomicdysregulation (e.g., edema, alteration in blood flow and hyperhidrosis)associated with trophic skin changes (hair and nail growth abnormalitiesand cutaneous ulceration).

Further types of pain contemplated for treatment include, but are notlimited to, those described in U.S. Patent Publication No. 2005/0203142,published Sep. 15, 2005, which is incorporated in its entirety herein byreference.

Examples of macular degeneration (MD) and related syndromes include, butare not limited to, those described in U.S. Patent Publication No.2004/0091455, published May 13, 2004, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, atrophic (dry) MD, exudative (wet) MD, age-relatedmaculopathy (ARM), choroidal neovascularisation (CNV), retinal pigmentepithelium detachment (PED), and atrophy of retinal pigment epithelium(RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0214328A1, published Sep.29, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, keratoses and relatedsymptoms, skin diseases or disorders characterized with overgrowths ofthe epidermis, acne, and wrinkles.

“Keratosis” refers to any lesion on the epidermis marked by the presenceof circumscribed overgrowths of the horny layer, including but notlimited to, actinic keratosis, seborrheic keratosis, keratoacanthoma,keratosis follicularis (Darier's disease), inverted follicularkeratosis, palmoplantar keratoderma (PPK, keratosis palmaris etplantaris), keratosis pilaris, and stucco keratosis. The term “actinickeratosis” also refers to senile keratosis, keratosis senilis, verrucasenilis, plana senilis, solar keratosis, keratoderma or keratoma. Theterm “seborrheic keratosis” also refers to seborrheic wart, senile wart,or basal cell papilloma. Keratosis is characterized by one or more ofthe following symptoms: rough appearing, scaly, erythematous papules,plaques, spicules or nodules on exposed surfaces (e.g., face, hands,ears, neck, legs and thorax), excrescences of keratin referred to ascutaneous horns, hyperkeratosis, telangiectasias, elastosis, pigmentedlentigines, acanthosis, parakeratosis, dyskeratosis, papillomatosis,hyperpigmentation of the basal cells, cellular atypia, mitotic figures,abnormal cell-cell adhesion, dense inflammatory infiltrates and smallprevalence of squamous cell carcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratosis, sign of Leser-Trélat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, Cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0239842A1, published Oct.27, 2005, which is incorporated in its entirety herein by reference.Specific examples include pulmonary hypertension and related disorders.Examples of pulmonary hypertension and related disorders include, butare not limited to: primary pulmonary hypertension (PPH); secondarypulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillarypulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonaryartery hypertension; idiopathic pulmonary hypertension; thromboticpulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy;functional classes I to IV pulmonary hypertension; and pulmonaryhypertension associated with, related to, or secondary to, leftventricular dysfunction, mitral valvular disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis,anomalous pulmonary venous drainage, pulmonary venoocclusive disease,collagen vascular disease, congenital heart disease, HIV virusinfection, drugs and toxins such as fenfluramine, congenital heartdisease, pulmonary venous hypertension, chronic obstructive pulmonarydisease (COPD), interstitial lung disease, sleep-disordered breathing,alveolar hypoventilation disorder, chronic exposure to high altitude,neonatal lung disease, alveolar-capillary dysplasia, sickle celldisease, other coagulation disorder, chronic thromboemboli, connectivetissue disease, lupus including systemic and cutaneous lupus,schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but are not limited to,those described in U.S. Patent Publication No. 2005/0100529, publishedMay 12, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, mesothelioma,asbestosis, malignant pleural effusion, benign exudative effusion,pleural plaques, pleural calcification, diffuse pleural thickening,rounded atelectasis, fibrotic masses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2006/0154880, published Jul.13, 2006, which is incorporated in its entirety herein by reference.Parasitic diseases include diseases and disorders caused by humanintracellular parasites such as, but not limited to, P. falciparum, P.ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica,L. major, L. tropica, L. mexicana, L. braziliensis, T Gondii, B.microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E.histolytica, I. belli, S. mansonii, S. haematobium, Trypanosoma spp.,Toxoplasma spp., and O. volvulus. Other diseases and disorders caused bynon-human intracellular parasites such as, but not limited to, Babesiabovis, Babesia canis, Banesia gibsoni, Besnoitia darlingi, Cytauxzoonfelis, Eimeria spp., Hammondia spp., and Theileria spp., are alsoencompassed. Specific examples include, but are not limited to, malaria,babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis,meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. patent application Ser. No. 11/289,723, filedNov. 30, 2005. Specific examples include, but are not limited to,adenosine deaminase deficiency, antibody deficiency with normal orelevated Igs, ataxia-telangiectasia, bare lymphocyte syndrome, commonvariable immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. Patent Publication No. 2005/0143344, published Jun.30, 2005, which is incorporated in its entirety herein by reference.Specific examples include, but are not limited to, amyotrophic lateralsclerosis, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, multiple sclerosis, other neuroimmunological disorders such asTourette syndrome, delirium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. Patent Publication No. 2006/0122228,published Jun. 8, 2006, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, CNSinjury/damage and related syndromes, including, but not limited to,primary brain injury, secondary brain injury, traumatic brain injury,focal brain injury, diffuse axonal injury, head injury, concussion,post-concussion syndrome, cerebral contusion and laceration, subduralhematoma, epidermal hematoma, post-traumatic epilepsy, chronicvegetative state, complete spinal cord injury (SCI), incomplete SCI,acute SCI, subacute SCI, chronic SCI, central cord syndrome,Brown-Séquard syndrome, anterior cord syndrome, conus medullarissyndrome, cauda equina syndrome, neurogenic shock, spinal shock, alteredlevel of consciousness, headache, nausea, emesis, memory loss,dizziness, diplopia, blurred vision, emotional lability, sleepdisturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but are not limited to, viral,genetic, allergic, and autoimmune diseases. Specific examples include,but are not limited to, HIV, hepatitis, adult respiratory distresssyndrome, bone resorption diseases, chronic pulmonary inflammatorydiseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxicshock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusioninjury, meningitis, psoriasis, fibrotic disease, cachexia, graft versushost disease, graft rejection, auto-immune disease, rheumatoidspondylitis, Crohn's disease, ulcerative colitis, inflammatory boweldisease, multiple sclerosis, systemic lupus erythematosus, erythemanodosum leprosum (ENL) in leprosy, radiation damage, cancer, asthma, orhyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. Patent Publication No. 2002/0054899,published May 9, 2002, which is incorporated in its entirety herein byreference. Specific examples include, but are not limited to, all formsof conditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary bypass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts.

Exemplary major systemic arteries that may be in need of treatment,include, for example, Axillary, Brachial, Brachiocephalic, Celiac,Common carotid, Common iliac, Coronary, Deep femoral, Digital, Dorsalispedis, External carotid, External iliac, Femoral, Gastric, Hepatic,Inferior mesenteric, Internal carotid, Internal iliac, Left gastric,Middle sacral, Ovarian, Palmar arch, Peroneal, Popliteal, Posteriortibial, Pulmonary, Radial, Renal, Splenic, Subclavian, Superiormesenteric, Testicular, and Ulnar.

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. Patent Publication No.2005/0222209A1, published Oct. 6, 2005, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, snoring, sleep apnea, insomnia, narcolepsy, restless legsyndrome, sleep terrors, sleep walking, sleep eating, and dysfunctionalsleep associated with chronic neurological or inflammatory conditions.Chronic neurological or inflammatory conditions, include, but are notlimited to, complex regional pain syndrome (CRPS), chronic low backpain, musculoskeletal pain, arthritis, radiculopathy, pain associatedwith cancer, fibromyalgia, chronic fatigue syndrome, visceral pain,bladder pain, chronic pancreatitis, neuropathies (diabetic,post-herpetic, traumatic or inflammatory), and neurodegenerativedisorders such as Parkinson's disease,

Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiplesclerosis, Huntington's disease, bradykinesia, muscle rigidity,parkinsonian tremor, parkinsonian gait, motion freezing, depression,defective long-term memory, Rubinstein-Taybi syndrome (RTS), dementia,postural instability, hypokinetic disorders, synuclein disorders,multiple system atrophies, striatonigral degeneration,olivopontocerebellar atrophy, Shy-Drager syndrome, motor neuron diseasewith parkinsonian features, Lewy body dementia, Tau pathology disorders,progressive supranuclear palsy, corticobasal degeneration,frontotemporal dementia, amyloid pathology disorders, mild cognitiveimpairment, Alzheimer's disease with parkinsonism, Wilson disease,Hallervorden-Spatz disease, Chédiak-Higashi disease, SCA-3spinocerebellar ataxia, X-linked dystonia parkinsonism, prion disease,hyperkinetic disorders, chorea, ballismus, dystonia tremors, CNS trauma,and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. Patent Publication No.2005/0143420A1, published Jun. 30, 2005, which is incorporated in itsentirety herein by reference. Specific examples include, but are notlimited to, hemoglobinopathy, sickle cell anemia, and any otherdisorders related to the differentiation of CD34+ cells.

Examples of TNF-α related disorders include, but are not limited to,those described in WO 2014/004990, WO 98/03502, and WO 98/54170, all ofwhich are incorporated herein in their entireties by reference. Specificexamples include, but are not limited to: endotoxemia or toxic shocksyndrome; cachexia; adult respiratory distress syndrome; bone resorptiondiseases such as arthritis; hypercalcemia; graft versus host reaction;cerebral malaria; inflammation; tumor growth; chronic pulmonaryinflammatory diseases; reperfusion injury; myocardial infarction;stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIVinfection and AIDS; other disorders such as rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and otherarthritic conditions, septic shock, sepsis, endotoxic shock, graftversus host disease, wasting, ulcerative colitis, multiple sclerosis,systemic lupus erythematosus, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as endotoxic shock,hemodynamic shock and sepsis syndrome, post-ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, graft rejection, oncogenic or cancerousconditions, asthma, autoimmune disease, radiation damages, and hyperoxicalveolar injury; viral infections, such as those caused by the herpesviruses; viral conjunctivitis; or atopic dermatitis.

In other aspects, the use of compounds provided herein in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in U.S. PatentPublication No. 2007/0048327, which is incorporated herein in itsentirety by reference, is also encompassed. These embodiments alsorelate to the uses of compounds provided herein in combination withvaccines to treat or prevent cancer or infectious diseases, and othervarious uses of immunomodulatory compounds such as reduction ordesensitization of allergic reactions.

Additional medical disorders for treatment include those described ininternational patent application publication nos. WO 2012/125459 and WO2012/125475, each of which is hereby incorporated by reference.

In one aspect, the invention provides a method for treating a disorderselected from the group consisting of angiogenesis and acytokine-related disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a deuterium-enrichedisoindolinonyl-piperidinonyl conjugate or a deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugate described herein to treatthe disorder.

In one aspect, the invention provides a method of treating cancer in apatient, comprising administering to a patient in need thereof atherapeutically effective amount of a deuterium-enrichedisoindolinonyl-piperidinonyl conjugate or a deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugate described herein to treatthe cancer.

In certain embodiments, the cancer is a cancer of the bladder, bone,blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye,head, kidney, liver, lymph node, lung, mouth, neck, ovary, pancreas,prostate, rectum, stomach, testis, throat, or uterus.

In certain embodiments, the cancer is an advanced malignancy,amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiplebrain metastases, glioblastoma multiforme, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes Ccolorectal cancer, Dukes D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acutemyeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse largeB-cell lymphoma, low grade follicular lymphoma, malignant melanoma,malignant mesothelioma, malignant pleural effusion mesotheliomasyndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologicsarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis,Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificansprogressiva, hormone refractory prostate cancer, resected high-risk softtissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen-independent prostate cancer, androgen-dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

In one aspect, the invention provides a method of treating a disorderselected from the group consisting of an immune disorder and aninflammatory disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a deuterium-enrichedisoindolinonyl-piperidinonyl conjugate or a deuterium-enrichedoxoquinazolin-3(4H)-yl-piperidinonyl conjugate described herein to treatthe disorder.

In certain embodiments, the disorder is Sjogren's syndrome, ANCA-inducedvasculitis, Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid antibody syndrome, antiphospholipid syndrome, asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatricialpemphigoid, cold agglutinin disease, Degos disease, dermatitishepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome,Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis,idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Meniere's disease, mixedconnective tissue disease, morphea, narcolepsy, neuromyotonia, apediatric autoimmune neuropsychiatric disorder, pemphigus vulgaris,pernicious anemia, polyarteritis nodosa, polychondritis, polymyalgiarheumatica, primary agammaglobulinemia, primary biliary cirrhosis,Raynaud's disease, Reiter's syndrome, relapsing polychondritis,rheumatic fever, stiff-person syndrome, Takayasu's arteritis, temporalarteritis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis.

In certain embodiments, the disorder is systemic lupus erythematosus,scleroderma, Sjogren's syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, or myasthenia gravis.

Additional disorders and methods of treatment are disclosed in U.S. Pat.No. 8,518,972, U.S. Patent Publication Nos. 2013/0324518 and2015/0119435, and international patent application publications WO2011/100380 and WO 2014/004990; all of which are hereby incorporated byreference in their entireties.

In one aspect, the present invention provides a method of treating adisorder selected from the group consisting of cancer, an immunedisorder, and an inflammatory disorder, comprising administering to apatient in need thereof a therapeutically effective amount of adeuterium-enriched isoindolinonyl-piperidinonyl conjugate oroxoquinazolin-3(4H)-yl-piperidinonyl conjugate described herein to treatthe disorder.

In certain embodiments, the disorder is cancer. In certain embodiments,the cancer is a cancer of the bladder, bone, blood, brain, breast,cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver,lymph node, lung, mouth, neck, ovary, pancreas, prostate, rectum,stomach, testis, throat, or uterus. In certain embodiments, the canceris an advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastases, glioblastoma multiforme,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C colorectal cancer, Dukes D colorectal cancer,unresectable colorectal carcinoma, metastatic hepatocellular carcinoma,Kaposi's sarcoma, acute myeloblastic leukemia, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-celllymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma,malignant melanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressiva, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen-independentprostate cancer, androgen-dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, or leiomyoma.

In certain embodiments, the disorder is an immune disorder.

In certain embodiments, the disorder is an inflammatory disorder.

In certain embodiments, the disorder is Sjogren's syndrome, ANCA-inducedvasculitis, Addison's disease, alopecia areata, ankylosing spondylitis,antiphospholipid antibody syndrome, antiphospholipid syndrome, asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatricialpemphigoid, cold agglutinin disease, Degos disease, dermatitishepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome,Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis,idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Meniere's disease, mixedconnective tissue disease, morphea, narcolepsy, neuromyotonia, apediatric autoimmune neuropsychiatric disorder, pemphigus vulgaris,pernicious anemia, polyarteritis nodosa, polychondritis, polymyalgiarheumatica, primary agammaglobulinemia, primary biliary cirrhosis,Raynaud's disease, Reiter's syndrome, relapsing polychondritis,rheumatic fever, stiff-person syndrome, Takayasu's arteritis, temporalarteritis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis.

In certain embodiments, the disorder is systemic lupus erythematosus,scleroderma, Sjogren's syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, or myasthenia gravis.

Still other collections of medical disorders for treatment includeasthma, autoimmune diseases, cancers, ciliopathies, cleft palate,diabetes, heart disease, hypertension, inflammatory bowel disease,mental retardation, mood disorder, obesity, refractive error,infertility, Angelman syndrome, celiac disease, Charcot-Marie-Toothdisease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis,hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria,polycystic kidney disease, (PKD1 or PKD2), Prader-Willi syndrome,sickle-cell disease, Tay-Sachs disease, Turner syndrome, Alzheimer'sdisease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexianervosa, anxiety disorder, atherosclerosis, attention deficithyperactivity disorder, autism, bipolar disorder, chronic fatiguesyndrome, chronic obstructive pulmonary disease, Crohn's disease,coronary heart disease, dementia, depression, diabetes mellitus type 1,diabetes mellitus type 2, epilepsy. Guillain-Barre syndrome, irritablebowel syndrome, lupus, metabolic syndrome, multiple sclerosis,myocardial infarction, obesity, obsessive-compulsive disorder, panicdisorder, Parkinson's disease, psoriasis, rheumatoid arthritis,sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourettesyndrome, vasculitis, aceruloplasminemia, achondrogenesis type II,achondroplasia, acrocephaly. Gaucher disease type 2, acute intermittentporphyria, Canavan disease, adenomatous Polyposis Coli, ALA dehydratasedeficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome,adrenoleukodystrophy, ALA-D porphyria, alkaptonuria, Alexander disease,alkaptonuric ochronosis, alpha-1 antitryp sin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstromsyndrome, amelogenesis imperfecta, Anderson-Fabry disease, androgeninsensitivity syndrome, anemia, angiokeratoma corporis diffusum,angiomatosis retinae (von Hippel-Lindau disease), Apert syndrome,arachnodactyly (Marfan syndrome), Stickler syndrome, arthrochalasismultiplex congenital (Ehlers-Danlos syndrome, arthrochalasia type),ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension,Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutisgyrata syndrome, Mediterranean fever, familial Benjamin syndrome,beta-thalassemia, bilateral acoustic neurofibromatosis(neurofibromatosis type II), factor V Leiden thrombophilia,Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome,X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turnersyndrome), Bourneville disease (tuberous sclerosis), prion disease,Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta),Rubinstein-Taybi syndrome, bronze diabetes/bronzed cirrhosis(hemochromatosis), bulbospinal muscular atrophy (Kennedy's disease),Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD chronicgranulomatous disorder, campomelic dysplasia, biotinidase deficiency,cardiomyopathy (Noonan syndrome), Cri du chat, CAVD (congenital absenceof the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP(congenital erythropoietic porphyria), cystic fibrosis, congenitalhypothyroidism, chondrodystrophy syndrome (achondroplasia),otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia,Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome,Cockayne syndrome (familial adenomatous polyposis), congenitalerythropoietic porphyria, congenital heart disease,methemoglobinemia/congenital methemoglobinaemia, achondroplasia,connective tissue disease, conotruncal anomaly face syndrome, Cooley'sanemia (beta-thalassemia), copper storage disease (Wilson's disease),copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cowden syndrome,Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophyDuchenne and Becker types (DBMD), Usher syndrome, degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbedisease), Di George's syndrome, dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoieticprotoporphyria, erythroid 5-aminolevulinate synthetase deficiency,erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, giant cellhepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), Hallgren syndrome, sickle cell anemia, hemophilia,hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (vonHippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), hyperandrogenism, hypochondroplasia,hypochromic anemia, immune system disorders, Insley-Astley syndrome,Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, kidneydiseases, including hyperoxaluria, Klinefelter's syndrome, Kniestdysplasia, lacunar dementia, Langer-Saldino achondrogenesis, ataxiatelangiectasia, Lynch syndrome, lysyl-hydroxylase deficiency,Machado-Joseph disease, metabolic disorders, movement disorders,Mowat-Wilson syndrome, Muenke syndrome, multiple neurofibromatosis,Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemmam-Pickdisease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease,Peutz-Jeghers syndrome, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson-Gilford progeria syndrome),progressive chorea, progressive muscular atrophy, spinal muscularatrophy, propionic acidemia, protoporphyria, proximal myotonicdystrophy, pulmonary arterial hypertension, PXE (pseudoxanthomaelasticum), Rb (retinoblastoma), Recklinghausen disease(neurofibromatosis type I), recurrent polyserositis, retinal disorders,retinoblastoma, RFALS type 3, Ricker syndrome, Riley-Day syndrome,Roussy-Levy syndrome, severe achondroplasia with developmental delay andacanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast,leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose(tuberous sclerosis), SDAT, SED congenital (spondyloepiphyseal dysplasiacongenita), SED Strudwick (spondyloepimetaphyseal dysplasia, Strudwicktype), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Strudwicktype (spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzensyndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome,South-African genetic porphyria (variegate porphyria), infantile-onsetascending hereditary spastic paralysis, speech and communicationdisorders, sphingolipidosis, spinocerebellar ataxia, Stickler syndrome,stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency,beta-thalassemia, thyroid disease, tomaculous neuropathy (hereditaryneuropathy with liability to pressure palsies), Treacher-Collinssyndrome, triplo X syndrome (triple X syndrome), trisomy 21 (Downsyndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visionimpairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburgsyndrome, Warburg-Sjo-Fledelius syndrome, Weissenbacher-Zweymullersyndrome, Wolf-Hirschhom syndrome, Wolff periodic disease, or Xerodennapigmentosum. In certain embodiments, the disorder for treatment is acancer (e.g., a squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas; cancerof the bladder, bowel, breast, cervix, colon, esophagus, head, kidney,liver, lung, neck, ovary, pancreas, prostate, and stomach; a leukemia; abenign or malignant lymphoma; a benign or malignant melanoma; amyeloproliferative disease; a sarcoma; bowel cancer, breast cancer,prostate cancer, cervical cancer, uterine cancer, lung cancer, ovariancancer, testicular cancer, thyroid cancer, astrocytoma, esophagealcancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer,melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or ateratocarcinoma).

Another aspect of the invention provides a method of treating orpreventing a disease characterized by oxidative stress. The methodcomprises administering to a patient in need thereof adeuterium-enriched compound described herein to treat or prevent thedisease characterized by oxidative stress. Exemplary diseasescharacterized by oxidative stress include, for example, cancer, ahyperproliferative cell growth condition, Parkinson's disease,Alzheimer's disease, atherosclerosis, heart failure (includingcongestive heart failure), myocardial infarction, schizophrenia, bipolardisorder, fragile X syndrome, sickle cell disease, chronic fatiguesyndrome, aging (including aging by induction of mitohormesis), diabetes(e.g., type I diabetes) and vascular disease.

Dosages

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, vary depending on factors suchas: specific indication to be treated; age and condition of a patient;and amount of second active agent used, if any. Generally, a compoundprovided herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

Second Active Agents

A compound provided herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions provided herein. Certain combinations may worksynergistically in the treatment of particular types of diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, can also work to alleviateadverse effects associated with certain second active agents, and viceversa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransferase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCl); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Perjeta®)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin®)); VEGFR inhibitors (such as, forexample, Flk-1 specific kinase inhibitors, SU5416 and PTK787/ZK222584);PI3K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated.

For instance, for the treatment of cancer, second active agents include,but are not limited to: semaxanib; cyclosporin; etanercept; doxycycline;bortezomib; acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; albomycin; ametantrone acetate;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycinsulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib; chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitotane; mitoxantrone hydrochloride; mycophenolic acid;nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozotocin; sulofenur; talisomycin; tecogalan sodium;taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide;teroxirone; testolactone; thiamiprine; thioguanine; thiotepa;tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to:20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogens;antiestrogens; antineoplaston; antisense oligonucleotides; aphidicolinglycinate; apoptosis gene modulators; apoptosis regulators; apurinicacid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;capecitabine; carboxyamidotriazole; cartilage-derived angiogenesisinhibitor; carzelesin; casein kinase inhibitors; castanospermine;cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide;cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin-816; crisnatol; cryptophycin-8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dihydrotaxol; dioxamycin; docetaxel; docosanol; dolasetron;doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorubicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib(Gleevec®), imiquimod; immunostimulant peptides; insulin-like growthfactor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalichondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maytansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;fibroblast growth factor-saporin mitotoxin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryllipid A+myobacterium cell wall skeleton; mopidamol; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; Nitrullyn; oblimersen (Genasense®);O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron hydrochloride; oracin; oral cytokine inducer;ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxelanalogues; paclitaxel derivatives; palau′amine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phosphatase inhibitors; picibanil; pilocarpine hydrochloride;pirarubicin; piritrexim; placetin A; placetin B; plasminogen activatorinhibitor; platinum complex; platinum compounds; platinum-triaminecomplex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;prostaglandin J2; proteasome inhibitors; protein A-based immunemodulator; protein kinase C inhibitor; microalgal protein kinase Cinhibitors; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylatedhemoglobin polyoxyethylene conjugate; Raf antagonists; raltitrexed;ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors;Ras-GAP inhibitor; demethylated retelliptine; rhenium-186 etidronate;rhizoxin; ribozymes; RH retinamide; rohitukine; romurtide; roquinimex;rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;sargramostim; SDI-1 mimetics; semustine; senescence derived inhibitor 1;sense oligonucleotides; signal transduction inhibitors; sizofuran;sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol;somatomedin-binding protein; sonermin; sparfosic acid; spicamycin D;spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide;stromelysin inhibitors; sulfinosine; superactive vasoactive intestinalpeptide antagonist; suradista; suramin; swainsonine; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb(2H); and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatin, temozolomide (Temodar®),cyclophosphamide, carboplatin, procarbazine, Gliadel®, tamoxifen,topotecan, methotrexate, Taxol®, taxotere, fluorouracil, leucovorin,irinotecan, Xeloda®, CPT-11, interferon alpha, pegylated interferonalpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa,fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol,paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine,zoledronic acid, pamitronate, Biaxin®, busulfan, prednisone,bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®),paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate(Emcyt®), sulindac, and etoposide.

In another aspect, examples of specific second agents according to theindications to be treated can be found in the following references, allof which are incorporated herein in their entireties: U.S. Pat. Nos.6,281,230 and 5,635,517; U.S. Patent Publication Nos. 2004/0220144,2004/0087546, 2005/0203142, 2004/0091455, 2005/0100529, 2005/0214328,2005/0239842, 2006/0154880, 2006/0122228, 2005/0143344, and2006/0188475.

Examples of second active agents that may be used for the treatment ofpain include, but are not limited to, conventional therapeutics used totreat or prevent pain such as antidepressants, anticonvulsants,antihypertensives, anxiolytics, calcium channel blockers, musclerelaxants, non-narcotic analgesics, opioid analgesics,anti-inflammatories, COX-2 inhibitors, immunomodulatory agents,alpha-adrenergic receptor agonists or antagonists, immunosuppressiveagents, corticosteroids, hyperbaric oxygen, ketamine, other anestheticagents, NMDA antagonists, and other therapeutics found, for example, inthe Physician's Desk Reference 2003. Specific examples include, but arenot limited to, salicylic acid acetate (Aspirin®), celecoxib(Celebrex®), Enbrel®, ketamine, gabapentin (Neurontin®), phenytoin(Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®),valproic acid (Depakene®), morphine sulfate, hydromorphone, prednisone,griseofulvin, penthonium, alendronate, diphenhydramine, guanethidine,ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO),clonidine (Catapres®), bretylium, ketanserin, reserpine, droperidol,atropine, phentolamine, bupivacaine, lidocaine, acetaminophen,nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine(Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®), fluoxetine(Prozac®), sertraline (Zoloft®), naproxen, nefazodone (Serzone®),venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®),mexiletine, nifedipine, propranolol, tramadol, lamotrigine, vioxx,ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen,tizanidine, and phenoxybenzamine.

Examples of second active agents that may be used for the treatment ofmacular degeneration and related syndromes include, but are not limitedto, a steroid, a light sensitizer, an integrin, an antioxidant, aninterferon, a xanthine derivative, a growth hormone, a neutrotrophicfactor, a regulator of neovascularization, an anti-VEGF antibody, aprostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatorycompound or an antiangiogenesis compound, or a combination thereof.Specific examples include, but are not limited to, verteporfin,purlytin, an angiostatic steroid, rhuFab, interferon-2-alpha,pentoxifylline, tin etiopurpurin, lucentis, lutetium chelates such asmotexafin lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin,6′-O-Mal-genistin, 6′-O—Ac-genistin, daidzein, daidzin,6′-O-Mal-daidzin, 6′-O—Ac-daidzin, glycitein, glycitin,6′-O-Mal-glycitin, biochanin A, formononetin (U.S. Pat. No. 6,001,368),triamcinolone acetonide, dexamethasone (U.S. Pat. No. 5,770,589),thalidomide, glutathione (U.S. Pat. No. 5,632,984), basic fibroblastgrowth factor (bFGF), transforming growth factor b (TGF-b),brain-derived neurotrophic factor (BDNF), plasminogen activator factortype 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly),Miravant SnET2, and RetisertTM implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment ofskin diseases include, but are not limited to, keratolytics, retinoids,α-hydroxy acids, antibiotics, collagen, botulinum toxin, interferon,steroids, and immunomodulatory agents. Specific examples include, butare not limited to, 5-fluorouracil, masoprocol, trichloroacetic acid,salicylic acid, lactic acid, ammonium lactate, urea, tretinoin,isotretinoin, antibiotics, collagen, botulinum toxin, interferon,corticosteroid, transretinoic acid and collagens such as human placentalcollagen, animal placental collagen, Dermalogen®, AlloDerm®, Cymetra®,Autologen®, Zyderm®, Zyplast®, Resoplast®, and Isolagen®.

Examples of second active agents that may be used for the treatment ofpulmonary hypertension and related disorders include, but are notlimited to, anticoagulants, diuretics, cardiac glycosides,calcium-channel blockers, vasodilators, prostacyclin analogues,endothelin antagonists, phosphodiesterase inhibitors (e.g., PDE Vinhibitors), endopeptidase inhibitors, lipid-lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin I2 (PGI2)), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat(Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin,L-arginine, iloprost, beraprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment ofasbestos-related disorders include, but are not limited to,anthracycline, platinum, alkylating agents, oblimersen (Genasense®),cyclophosphamide, Temodar®, carboplatin, procarbazine, Gliadel®,tamoxifen, topotecan, methotrexate, taxotere, irinotecan, capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, pamidronate, Biaxin®,busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), ganciclovir, adriamycin, bleomycin, hyaluronidase,mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment ofparasitic diseases include, but are not limited to, chloroquine,quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline,clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquine,proguanil, atovaquone, azithromycin, suramin, pentamidine, melarsoprol,nifurtimox, benznidazole, amphotericin B, pentavalent antimony compounds(e.g., sodium stibogluconate), interferon gamma, itraconazole, acombination of dead promastigotes and BCG, leucovorin, corticosteroids,sulfonamide, spiramycin, IgG (serology), trimethoprim, andsulfamethoxazole.

Examples of second active agents that may be used for the treatment ofimmunodeficiency disorders include, but are not limited to: antibiotics(therapeutic or prophylactic) such as, but not limited to, ampicillin,tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, anderythromycin; antivirals such as, but not limited to, amantadine,rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma;immunologic enhancing drugs such as, but not limited to, levamisole andisoprinosine; biologics such as, but not limited to, gammaglobulin,transfer factor, interleukins, and interferons; hormones such as, butnot limited to, thymic hormones; and other immunologic agents such as,but not limited to, B cell stimulators (e.g., BAFF/BlyS), cytokines(e.g., IL-2, IL-4, and IL-5), growth factors (e.g., TGF-α), antibodies(e.g., anti-CD40 and IgM), oligonucleotides containing unmethylated CpGmotifs, and vaccines (e.g., viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment ofCNS disorders include, but are not limited to: opioids; a dopamineagonist or antagonist, such as, but are not limited to, Levodopa,L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine,benzatropine, pargyline, fenoldopam mesylate, cabergoline, pramipexoledihydrochloride, ropinirole, amantadine hydrochloride (Symmetrel®),selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet® CR; aMAO inhibitor, such as, but not limited to, iproniazid, clorgiline,phenelzine and isocarboxazid; a COMT inhibitor, such as, but not limitedto, tolcapone and entacapone; a cholinesterase inhibitor, such as, butnot limited to, physostigmine salicylate, physostigmine sulfate,physostigmine bromide, neostigmine bromide, neostigmine methylsulfate,ambenonium chloride, edrophonium chloride, tacrine, pralidoximechloride, obidoxime chloride, trimedoxime bromide, diacetyl monoxime,pyridostigmine, and demecarium bromide; an anti-inflammatory agent, suchas, but not limited to, naproxen sodium, diclofenac sodium, diclofenacpotassium, celecoxib, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, rofecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenolate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbiprofen, oxaprozin, piroxicam, ampiroxicam, droxicam,pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine,aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate,auranofin, methotrexate, colchicine, allopurinol, probenecid,sulfinpyrazone and benzbromarone or betamethasone and otherglucocorticoids; and an antiemetic agent, such as, but not limited to,metoclopramide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and a mixture thereof.

Examples of second active agents that may be used for the treatment ofCNS injuries and related syndromes include, but are not limited to,immunomodulatory agents, immunosuppressive agents, antihypertensives,anticonvulsants, fibrinolytic agents, antiplatelet agents,antipsychotics, antidepressants, benzodiazepines, buspirone, amantadine,and other known or conventional agents used in patients with CNSinjury/damage and related syndromes. Specific examples include, but arenot limited to: steroids (e.g., glucocorticoids, such as, but notlimited to, methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, ibuprofen, ketoprofen, nabumetone, rofecoxib,methotrexate, leflunomide, sulfasalazine, gold salts, Rho-D ImmuneGlobulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus,basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methylsalicylate, diflunisal, salsalate, olsalazine, sulfasalazine,acetaminophen, indomethacin, mefenamic acid, meclofenamate sodium,tolmetin, ketorolac, dichlofenac, flurbiprofen, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, colchicine,allopurinol, probenecid, sulfinpyrazone and benzbromarone; a cAMP analogincluding, but not limited to, db-cAMP; an agent comprising amethylphenidate drug, which comprises 1-threo-methylphenidate,d-threo-methylphenidate, dl-threo-methylphenidate,1-erythro-methylphenidate, d-erythro-methylphenidate,dl-erythro-methylphenidate, and a mixture thereof; and a diuretic agentsuch as, but not limited to, mannitol, furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment ofdysfunctional sleep and related syndromes include, but are not limitedto, a tricyclic antidepressant agent, a selective serotonin reuptakeinhibitor, an antiepileptic agent (gabapentin, pregabalin,carbamazepine, oxcarbazepine, levetiracetam, topiramate), anantiaryhthmic agent, a sodium channel blocking agent, a selectiveinflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin®, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzatropine, pargyline,fenoldopam mesylate, cabergoline, pramipexole dihydrochloride,ropinirole, amantadine hydrochloride (Symmetrel®), selegilinehydrochloride, carbidopa, pergolide mesylate, Sinemet® CR, iproniazid,clorgiline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine salicylate, physostigmine sulfate, physostigmine bromide,neostigmine bromide, neostigmine methylsulfate, ambenonium chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxime, pyridostigmine, demecariumbromide, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, ibuprofen,ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, Rho-D Immune Globulin, mycophenolate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac,flurbiprofen, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopramide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment ofhemoglobinopathy and related disorders include, but are not limited to:interleukins, such as IL-2 (including recombinant IL-2 (“r1L2”) andcanarypox IL-2), IL-10, IL-12, and IL-18; interferons, such asinterferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferonalfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;hydroxyurea; butyrate or butyrate derivatives; nitrous oxide;hydroxyurea; Nicosan (see U.S. Pat. No. 5,800,819); Gardos channelantagonists such as clotrimazole and triaryl methane derivatives;deferoxamine; protein C; and transfusions of blood, or of a bloodsubstitute such as Hemospan® or Hemospan® PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, and the second activeagents to a patient can occur simultaneously or sequentially by the sameor different routes of administration. The suitability of a particularroute of administration employed for a particular active agent willdepend on the active agent itself (e.g., whether it can be administeredorally without decomposing prior to entering the blood stream) and thedisease being treated. One route of administration for compoundsprovided herein is oral. Routes of administration for the second activeagents or ingredients are known to those of ordinary skill in the art.See, e.g., Physicians' Desk Reference (60^(th) Ed., 2006).

In another aspect, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated, the severity and stage of disease, and theamount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

Cycling Therapy

In certain aspects, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in another aspect, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another aspect encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another aspect, a compound provided herein isadministered for a greater number of cycles than would typically causedose-limiting toxicity in a patient to whom a second active ingredientis not also being administered.

In another aspect, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In another aspect, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another aspect, thecombination of a compound provided herein and a second active ingredientis administered by intravenous infusion over about 90 minutes everycycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all aspects of the invention maybe taken in conjunction with any other aspect or aspects to describeadditional aspects. It is also to be understood that each individualelement of the aspects is intended to be taken individually as its ownindependent aspect. Furthermore, any element of an aspect is meant to becombined with any and all other elements from any aspect to describe anadditional aspect.

Manufacture of Medicaments

Another aspect of the invention provides for the use of adeuterium-enriched compound described herein for the manufacture of amedicament. The medicament may be for treating one or more of themedical disorders described herein, such as cancer.

III. Dosing Considerations and Combination Therapy

Doses of a compound provided herein, or a pharmaceutically acceptablesalt thereof, vary depending on factors such as: specific indication tobe treated; age and condition of a patient; and amount of second activeagent used, if any. Generally, a compound provided herein, or apharmaceutically acceptable salt thereof, may be used in an amount offrom about 0.1 mg to about 1 g per day, or from about 0.1 mg to about500 mg per day, and can be adjusted in a conventional fashion (e.g., thesame amount administered each day of the treatment), in cycles (e.g.,one week on, one week off), or in an amount that increases or decreasesover the course of treatment. In other embodiments, the dose can be fromabout 1 mg to 1000 mg, from about 1 mg to about 450 mg, from about 0.1mg to about 150 mg, from about 1 mg to about 300 mg, from about 10 mg toabout 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg,or from about 1 mg to about 20 mg.

In certain aspects, the therapeutic agents provided herein arecyclically administered to a patient. Cycling therapy involves theadministration of an active agent for a period of time, followed by arest (i.e., discontinuation of the administration) for a period of time,and repeating this sequential administration. Cycling therapy can reducethe development of resistance to one or more of the therapies. Theseregimens can avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in another aspect, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another aspect encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another aspect, a compound provided herein isadministered for a greater number of cycles than would typically causedose-limiting toxicity in a patient to whom a second active ingredientis not also being administered.

In another aspect, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 1000 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 450 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 300 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In another aspect, a compound provided herein and a second activeingredient are administered orally or parenterally, with administrationof the compound provided herein occurring prior to (e.g., about 30 to 60minutes) the second active ingredient, during a cycle of four to sixweeks. In certain embodiments, the compound and second active agent areadministered as a single dosage or they are administered separately. Inanother aspect, the combination of a compound provided herein and asecond active ingredient is administered by intravenous infusion overabout 90 minutes every cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about three to about fourcycles.

Combination Therapy

A compound provided herein, or a pharmaceutically acceptable saltthereof, can be combined with other pharmacologically active compounds(“second active agents”) in methods and compositions provided herein.Certain combinations may work synergistically in the treatment ofparticular types of diseases or disorders, and conditions and symptomsassociated with such diseases or disorders. A compound provided herein,or a pharmaceutically acceptable salt thereof, can also work toalleviate adverse effects associated with certain second active agents,and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

IV. Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising adeuterium-enriched compound described herein and a pharmaceuticallyacceptable carrier. In certain embodiments, the pharmaceuticalcompositions comprise a therapeutically-effective amount of adeuterium-enriched compound described herein, formulated together withone or more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets (e.g., those targeted for buccal,sublingual, and/or systemic absorption), boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration by,for example, subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt thereof. Pharmaceutical compositionsand dosage forms can further comprise one or more excipients.Additionally, pharmaceutical compositions and dosage forms providedherein can comprise one or more additional active ingredients. Examplesof optional second, or additional, active ingredients are describedabove.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18^(th) Ed., MackPublishing, Easton Pa. (1990).

The suitability of a particular excipient may depend on the specificactive ingredients in the dosage form. For example, the decomposition ofsome active ingredients may be accelerated by some excipients such aslactose, or when exposed to water. Active ingredients that compriseprimary or secondary amines are particularly susceptible to suchaccelerated decomposition. Consequently, provided are pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or disaccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U. S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In another aspect,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients. Anhydrous pharmaceutical compositions anddosage forms can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms that comprise lactose and at least oneactive ingredient that comprises a primary or secondary amine arepreferably anhydrous if substantial contact with moisture and/orhumidity during manufacturing, packaging, and/or storage is expected. Ananhydrous pharmaceutical composition should be prepared and stored suchthat its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in another aspect, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, dose containers (e.g.,vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In another aspect, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg.Examples of dosages include, but are not limited to, 0.1, 1, 2, 5, 7.5,10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450,or 500 mg.

In another aspect, dosage forms comprise the second active ingredient inan amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated, and theamount(s) of a compound provided herein, and any optional additionalactive agents concurrently administered to the patient.

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18^(th) Ed., Mack Publishing, Easton Pa.(1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In another aspect, the invention provides oral dosage forms that aretablets or capsules, in which case solid excipients are employed. Inanother aspect, the tablets can be coated by standard aqueous ornon-aqueous techniques. Such dosage forms can be prepared by any of themethods of pharmacy. In general, pharmaceutical compositions and dosageforms are prepared by uniformly and intimately admixing the activeingredients with liquid carriers, finely divided solid carriers, orboth, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in anotheraspect, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. Inanother aspect, pharmaceutical compositions comprise from about 0.5 toabout 15 weight percent of disintegrant, or from about 1 to about 5weight percent of disintegrant. Disintegrants that can be used inpharmaceutical compositions and dosage forms include, but are notlimited to, agar-agar, alginic acid, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, crospovidone, polacrilin potassium,sodium starch glycolate, potato or tapioca starch, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof.Additional lubricants include, for example, a Syloid® silica gel(AEROSIL200, manufactured by W. R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPiano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In another aspect, the invention provides a solid oral dosage formcomprising a compound provided herein, anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

Active ingredients provided herein can also be administered bycontrolled release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated in its entirety herein by reference. Such dosage formscan be used to provide slow or controlled-release of one or more activeingredients using, for example, hydroxypropyl methyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active agents provided herein. In anotheraspect, the invention provides single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial.Administration of a parenteral dosage form bypasses a patient's naturaldefenses against contaminants, and thus, in these aspects, parenteraldosage forms are sterile or capable of being sterilized prior toadministration to a patient. Examples of parenteral dosage formsinclude, but are not limited to, solutions ready for injection, dryproducts ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions. Suitable vehicles that can be used to provide parenteraldosage forms are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated in itsentirety herein by reference.

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18^(th) Eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4^(th) Ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In another aspect,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are nontoxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16^(th) and 18^(th) Eds., Mack Publishing,Easton Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other aspects, stearates can serve as a lipidvehicle for the formulation, as an emulsifying agent or surfactant, oras a delivery-enhancing or penetration-enhancing agent. In otheraspects, salts of the active ingredients can be used to further adjustthe properties of the resulting composition.

In another aspect, the active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another aspect, provided are kits which can simplifythe administration of appropriate amounts of active ingredients.

In another aspect, the invention provides a kit comprising a dosage formof a compound provided herein. Kits can further comprise additionalactive ingredients or a pharmacologically active mutant or derivativethereof, or a combination thereof. Examples of the additional activeingredients include, but are not limited to, those disclosed herein.

In other aspects, the kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

V. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The term “compound” refers to a quantity of molecules that is sufficientto be weighed, tested for its structural identity, and to have ademonstrable use (e.g., a quantity that can be shown to be active in anassay, an in vitro test, or in vivo test, or a quantity that can beadministered to a patient and provide a therapeutic benefit).

Unless indicated otherwise, when a D is specifically recited at aposition or is shown in a formula, this D represents a mixture ofhydrogen and deuterium where the amount of deuterium is about 100%(i.e., the abundance of deuterium ranges from greater than 90% up to100%). In certain embodiments, the abundance of deuterium in D is from95% to 100%, or from 97% to 100%.

The term “patient” refers to organisms to be treated by the methods ofthe present invention. Such organisms preferably include, but are notlimited to, mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and most preferably includes humans.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

“Therapeutically effective amount” includes an amount of a compound ofthe invention that is effective when administered alone or incombination to treat the desired condition or disorder. “Therapeuticallyeffective amount” includes an amount of the combination of compoundsclaimed that is effective to treat the desired condition or disorder.The combination of compounds can be additive and is preferably asynergistic combination. Synergy, as described, for example, by Chou andTalalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect ofthe compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower incidence of adverse side effects and/or toxicity, increasedefficacy, or some other beneficial effect of the combination comparedwith the individual components.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofthe basic residues. The pharmaceutically acceptable salts include theconventional quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. These salts canbe prepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed during subsequent purification.For example, such conventional non-toxic salts include, but are notlimited to, those derived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, bisulfonic, carbonic,citric, edetic, ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauric, lauryl sulfonic, maleic, malic,mandelic, methanesulfonic, napsylic, naphthylic, nitric, oleic, oxalic,palmitic, pamoic, pantothenic, phenylacetic, phosphoric,polygalacturonic, propionic, salicylic, stearic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and valeric.(See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm.Sci. 66:1-19.). In certain embodiments, the pharmaceutically acceptablesalt is a hydrochloric acid salt. In certain other embodiments, thepharmaceutically acceptable salt is a hydrobromic acid salt.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as oil/water orwater/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see e.g., Martin,Remington's Pharmaceutical Sciences, 15^(th) Ed., Mack Publ. Co.,Easton, Pa. (1975).

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

As a general matter, if a variable is not accompanied by a definition,then the previous definition of the variable controls.

Finally, the invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects and embodiments of theinvention noted herein. It is understood that any and all aspects of theinvention may be taken in conjunction with any other aspects and/orembodiments to describe additional aspects. It is also to be understoodthat each individual element of the aspects is intended to be takenindividually as its own independent aspect. Furthermore, any element ofan aspect is meant to be combined with any and all other elements fromany aspect to describe an additional aspect.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Preparation of D-dBET1

The compound D-dBET1 (shown above) was prepared according to theprocedures described below, as generally illustrated in the followingscheme. The first two steps were performed sequentially in one pot fromintermediate 5, prepared as described in Science (2015) vol. 348, pages1376-1381, to give amine D-10 as a trifluoroacetic acid salt. D-10 wasthen coupled with the acid of JQ1, prepared by hydrolysis of thetert-butyl ester group of JQ1, using standard peptide couplingconditions.

Part I—Synthesis of Amine D-10

(3R)-3-d₁-aminopiperidine-2,6-dione hydrochloride (123 mg, 0.74 mmol),sodium acetate (72.0 mg, 0.878 mmol), and tert-butyl[4-({[(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)oxy]acetyl}amino)butyl]carbamate(288 mg, 0.73 mmol) were combined in a 6 mL crimp cap microwave tubeequipped with a stir bar. The cap was crimped on, and the headspace wasswapped for dry nitrogen (purge/fill x3). Acetic acid-d₄ (1.7 mL) wasadded via syringe. The resulting slurry was lowered into a pre-heated80° C. oil bath and stirred for 2.5 days. The reaction mixture wascooled to room temperature, trifluoroacetic acid (TFA, 1.7 mL) wasadded, and the resulting mixture was stirred for 24 h to complete thedeprotection. The reaction mixture was then concentrated, and purifiedby reverse-phase chromatography (0 to 100% water+1.0% TFA (v/v) andacetonitrile+0.7% TFA (v/v)). Like fractions were combined,concentrated, and the residue was suspended in acetonitrile anddichloromethane before being reconcentrated to give D-10 as a brownsolid (225 mg, 59%). ¹H NMR analysis of these solids shows 86% Dincorporation at C(3) of the glutarimide. ¹H NMR (DMSO-d₆, 400 MHz) δ11.13 (1H, s), 8.03 (1H, t, J=6.0 Hz), 7.83 (1H, dd, J=7.3, 8.6 Hz),7.68 (3H, br s), 7.51 (1H, d, J=7.1 Hz), 7.40 (1H, d, J=8.3 Hz), 5.12(0.14H, dd, J=5.6, 12.9 Hz), 4.79 (2H, s), 3.1-3.3 (2H, m), 2.55-3.0(3H, m), 1.9-2.05 (1H, m), and 1.35-1.60 (4H, m). MS: ESI⁺ m/z (relativeintensity): 403.2 (4), 404.3 (41), 405.3 (100), 406.3 (74), 407.3 (14),and 408.3 (2).

Part II—Synthesis of JQ1-Acid

JQ1 (213.7 mg, 0.47 mmol) was weighed into a crimp cap microwave tube,equipped with a stir bar, and the cap was crimped on. The headspace wasswapped for dry nitrogen (purge/fill x3), and 4.0 M HCl in dioxane wasadded. The resulting suspension was sonicated until homogeneous. Thereaction was heated in a pre-heated 50° C. oil bath for ca. 25 minutes,at which point the reaction was complete by HPLC. The reaction mixturewas concentrated in vacuo, resuspended in ethyl acetate, sonicated to ahomogeneous suspension, and reconcentrated to give JQ1-Acid (240 mg) asa yellow solid that was used without purification.

Part III—Synthesis of D-dBET1

N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 89.3 mg, 0.235 mmol) and JQ1-Acid(114.7 mg, 0.223 mmol) were combined in a 10 mL pear-shaped flaskequipped with a stir bar and a capplug cap. The solids were dissolved inN,N-dimethylformamide (DMF, 2.1 mL) and N,N-diisopropyl-ethylamine(DIPEA, 120 μL, 069 mmol) with sonication. Formation of the activatedester was monitored by HPLC. After 35 minutes, HATU (19.2 mg, 0.051mmol) was added. The resulting solution was stirred for 2 minutes thend₁-N-(4-aminobutyl)-2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamidetrifluoroacetic acid salt (D-10 trifluoroacetic acid salt, 125.4 mg,0.2424 mmol) was added in a single portion, and the reaction wasmonitored by HPLC. After 30 minutes, DIPEA (120 μL, 0.69 mmol) wasadded, and the reaction was stirred for another 30 min. An additionalportion of D-10 trifluoroacetic acid salt (5.8 mg, 0.011 mmol) wasadded, and the reaction was stirred for an additional 75 minutes. Thecrude reaction mixture was precipitated by a subsurface addition intowater (25 mL), and extracted into ethyl acetate (50 mL×3). The combinedorganic extracts were washed with water (50 mL×2), and brine (50 mL),then dried with magnesium sulfate, filtered, and concentrated in vacuoto give a yellow-green semi-solid. This material was redissolved indichloromethane and reconcentrated to give D-dBET1 (127 mg, 72%) as ayellow foam. ¹H NMR (DMSO-d6, 400 MHz) δ 11.12 (1H, s), 8.20 (1H, br t,J=5.7 Hz), 7.98 (1H, br t, J=5.7 Hz), 7.81 (1H, dd, J=7.3, 8.3 Hz),7.35-7.53 (6H, m), 5.12 (0.13H, dd, J=5.6, 13.1 Hz), 4.78 (2H, s), 4.50(1H, dd, J=6.1, 7.8 Hz), 3.0-3.30 (6H, m), 2.65-2.72 (2H, m), 2.59 (3H,s), 2.39-2.42 (3H, m), 1.95-2.1 (3H, m), and 1.35-1.70 (7H, m). MS: ESIm/z (relative intensity): 785.2 (2), 786.3 (34), 787.3 (95), 788.3(100), 789.3 (68), 790.3 (42), 791.3 (13), 792.3 (4), 793.4 (1).

Example 2 Preparation and Separation of Enantiomers of dBET1

Racemic dBET1 having the natural distribution of isotopes wassynthesized as described by Bradner et al. in Science (2015) vol. 348,pages 1376-1381. The racemic dBET1 was subjected to chiral supercriticalfluid chromatography (SFC) to separate the individual enantiomers.Fractions containing each enantiomer (peak 1 and peak 2) were pooled andevaporated under reduced pressure, then dried overnight in vacuo to givea composition for the peak 1 enantiomer and composition for the peak 2enantiomer, each as solids (54 mg each). Both compositions were analyzedfor enantiomeric purity by analytical chiral SFC. Both compositions hada purity of at least 99.7% with an enantiomeric excess of 100% ee forthe peak 1 composition and 99.4% ee for the peak 2 composition.

Example 3 Analysis of Chiral Stability of (I) Deuterium-enriched dBET1and (II) dBET1 Having the Natural Distribution of Isotopes

Stability of the glutarimide chiral center in deuterium-enriched dBET1and in dBET1 having the natural distribution of isotopes was performed.Experimental procedures and results are described below.

Part I—Chiral Stability of dBET1 Having the Natural Distribution ofIsotopes

The chiral stability of enantiomers of dBET1 having the naturaldistribution of isotopes (hereinafter “protonated dBET1”) inphosphate-buffered saline (pH 7.4) was evaluated using quantitativechiral SFC with UV detection to quantify the reaction. Sinceracemization in non-chiral medium is independent of the chirality of thestarting material, the stability of a single enantiomer (peak 2 in theexample above) was evaluated. A stock solution of the enantiomercorresponding to peak 2 (see Example 2) in DMSO (24 mg of peak 2 in 1 mLof DMSO) was prepared. The solution (20 μL) was added to 4 mL of PBSbuffer. The mixture was homogenized and an aliquot (250 μL) takenimmediately. The aliquot was quenched by adding it to 500 μL of 5% (v/v)formic acid in methanol. The mixture was incubated at 25° C. Aliquotswere taken at preset time points and prepared as described above. Allsamples were analyzed by chiral SFC with UV detection (ChiralPak AS-H4.6×100 mm, 30% methanol+0.25% diethylamine in CO₂, flow rate 4 mL/min,100 bar, UV 254 nm, 5 μL injections).

Peaks corresponding to both enantiomers were integrated and theirrelative peak areas (expressed as % of total) were plotted. The resultsare shown in FIG. 1, which is a line graph showing relative peak areasof the enantiomers of protonated dBET1 (area(enantiomer)/sum of areas)as function of time upon incubation in PBS (pH=7.4) at 25° C.

The data was analyzed by numerical evaluation of the differentialequations describing the kinetics of inter-conversion betweenenantiomers peak 1 (p1) and peak 2 (p2) as shown in equations 1 to 3below.

$\begin{matrix}{{\frac{d\left\lbrack {p\; 1} \right\rbrack}{dt} = {{- {k_{12}\left\lbrack {p\; 1} \right\rbrack}} + {k_{21}\left\lbrack {p\; 2} \right\rbrack}}}{\frac{d\left\lbrack {p\; 2} \right\rbrack}{dt} = {{{k_{12}\left\lbrack {p\; 1} \right\rbrack} - {{k_{21}\left\lbrack {p\; 2} \right\rbrack}\left\lbrack {p\; 1} \right\rbrack} + \left\lbrack {p\; 2} \right\rbrack} = 1}}} & \left( {{equations}\mspace{14mu} 1\text{-}3} \right)\end{matrix}$where p1 and p2 are peak 1 and peak 2 and where k₁₂ and k₂₁ are theenantiomerization rate constants from peak 1 to peak 2 and peak 2 topeak 1, respectively.

In an achiral medium, racemization gives a 1:1 mixture of bothenantiomers and rate constants k₁₂ and k₂₁ are the same. Numericalevaluation was performed in Excel 2016 (Microsoft Corp) using the Solveradd-in to minimize the sum of the square of the difference betweencalculated and observed relative [p1] and [p2] concentrations normalizedto the observed relative concentration of the same enantiomer byadjusting the enantiomerization rate constant k=k₁₂=k₂₁ as discussedabove. By analysis of data obtained for up to 8h incubation, a rateconstant of 0.0157 h⁻¹ was obtained, which corresponds to anenantiomerization half-life of 44 h.

Thus, the racemization half-life (one half of the enantiomerizationhalf-life) for protonated dBET1 at 25° C. is 22 hours.

Part II—Deuterium/Hydrogen (D/II) Exchange in Deuterium-enriched dBET1

In order to evaluate the stability against racemization provided bydeuterium enrichment at the racemizable chiral center of the glutarimideportion of dBET1, a sample of racemic, deuterium-enriched dBET1 fromExample 1 (i.e., D-dBET1 from Example 1) was incubated in PBS (pH=7.4)at 25° C. in the presence of ethyl paraben as an internal standard. A 20μL solution of racemic, deuterium-enriched dBET1 (D-dBET1), aliquotedfrom 21.6 mg dissolved in 1 mL DMSO, was added to 4 mL of PBS (pH=7.4).The reaction was performed in duplicate. Aliquots were taken out atpreset times and quenched with methanol in the presence of acetic acid(250 μL aliquot quenched with 500 μL 5% (v/v) acetic acid in methanol).The samples were analyzed by HPLC/UV (10 μL injection) and LC/MS (1 μLinjection) using a reverse-phase column.

Since the reaction is performed in an achiral medium, the kinetics ofD/H exchange will be independent of the chirality of the startingmaterial. As a result, separation of the enantiomers of D-dBET1 prior tothe stability study is not required. UV analysis revealed that the areaof the chromatography peak corresponding to dBET1 (deuterated and/orprotonated) decreased as a function of the incubation time whennormalized to the area of the peak corresponding to the internalstandard. This observation demonstrates that the instability of thechiral center of the glutarimide portion of dBET1 at pH=7.4 is similarto what has been observed for the related parent molecule, pomalidomide(see Chirality (2003) vol. 15, pages 348-351).

Analysis of the mass spectrometry data corresponding to the dBET1 peakdid not show a change in the ratio of isotopic peaks as a function oftime. A change in the ratio is expected if D/H exchange is observedsince, for example, a peak at M+2, where M is the mass of themono-deuterated isotopomer of dBET1, would by D/H exchange disappear andgive a corresponding peak at M+1. Similarly, M+3 would give M+2, etc. Inthe data obtained from the present analysis, the isotopic distributionof deuterium-enriched dBET1 (D-dBET1) did not change significantly as afunction of incubation time, as shown by MS spectra data up to the finaltime point at 24h, as shown in FIG. 2 which provides mass spectra plotsshowing mass spectral isotopic ratio for deuterium-enriched dBET1(D-dBET1) incubated in PBS (pH=7.4) at 25° C., where FIG. 2 Part A isfor time=0 hours and FIG. 2 Part B is for time=24 hours, each inpositive ion mode with 785 and 807 the molecular weight of protonateddBET1+one proton and protonated dBET1+one sodium, respectively.

These studies demonstrate the stabilization effect achieved byincorporating deuterium at the racemizable chiral center of theglutarimide portion of dBET1. With deuterium enrichment at the chiralcenter of the glutarimide portion of dBET1, racemization issignificantly slowed from a racemization half-life of −22h at 25° C. inPBS (pH=7.4) for protonated dBET1 to a deuterium-hydrogen exchangehalf-life>>24h at 25° C. in PBS (pH=7.4) for deuterium-enriched dBET1(D-DBET1).

INCORPORATION BY REFERENCE

All references listed herein are individually incorporated in theirentirety by reference.

EQUIVALENTS

Numerous modifications and variations of the invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise that as specifically described herein.

The invention claimed is:
 1. A deuterium-enriched compound, wherein thecompound is selected from the group consisting of: (i) a compound ofFormula II represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%, (ii) acompound of Formula III represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%, (iii) acompound of Formula IV represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%, and (iv)a compound of Formula IV represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.
 2. Thecompound of claim 1, wherein the compound is a compound of Formula IIrepresented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.
 3. Thecompound of claim 2, wherein the compound is a compound of Formula II-Arepresented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 4. The compound of claim 2,wherein the compound is a compound of Formula II-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 5. The compound of claim 1,wherein the compound is a compound of Formula III represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.
 6. Thecompound of claim 5, wherein the compound is a compound of Formula III-Arepresented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 7. The compound of claim 5,wherein the compound is a compound of Formula III-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 8. The compound of claim 1,wherein the compound is a compound of Formula IV represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.
 9. Thecompound of claim 8, wherein the compound is a compound of Formula IV-Arepresented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 10. The compound of claim8, wherein the compound is a compound of Formula IV-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 11. The compound of claim1, wherein the compound is a compound of Formula V represented by:

or a pharmaceutically acceptable salt thereof; wherein Z is H or D,provided that the abundance of deuterium in Z is at least 30%.
 12. Thecompound of claim 11, wherein the compound is a compound of Formula V-Arepresented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 13. The compound of claim11, wherein the compound is a compound of Formula V-B represented by:

or a pharmaceutically acceptable salt thereof; wherein the compound hasa stereochemical purity of at least 75% enantiomeric excess at thecarbon atom bearing variable Z; and Z is H or D, provided that theabundance of deuterium in Z is at least 30%.
 14. The compound of claim5, wherein the abundance of deuterium in Z is at least 90%.
 15. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 16. A method of treating a disorderselected from the group consisting of cancer, an immune disorder, and aninflammatory disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1 totreat the disorder.
 17. The method of claim 16, wherein the disorder iscancer.
 18. The compound of claim 5, wherein the abundance of deuteriumin Z is at least 90%.
 19. The compound of claim 8, wherein the abundanceof deuterium in Z is at least 90%.
 20. The compound of claim 11, whereinthe abundance of deuterium in Z is at least 90%.